Sjgren's syndrome (SS) is an autoimmune disease of unknown etiology. It is the second most common autoimmune disease with predominance noted in females compared to makes (9:1). Strong evidence exists supporting a viral etiology of SS, but as of yet a direct cause and effect relationship has not been established. It is our hypothesis that more than one virus may be able to trigger the development of SS. To get a better picture of the viruses present in salivary glands of SS patients, we used a custom viral microarray chip to identify virus profiles in the salivary glands of SS patients and healthy volunteers. Using this platform, we have identified a distinct cohort of SS patients positive for Hepatitis Delta Virus (HDV). Our preliminary data has revealed not only the presence of HDV sequence in salivary glands of a subset of SS patients, but also the presence of HDV antigen. Making this viral profile more unique, these patients have tested negative for Hepatitis B virus antigen and antibody, the only known helper virus of HDV. This proposal aims to define the role of HDV in SS and determine if a direct cause-and-effect relationship exists between expression of the HDV antigen or genome and altered salivary gland function. In vitro studies will evaluate the impact of HDV antigen or genome expression and cellular function in salivary gland cell lines. Next, in vivo studies will evaluate expression of HDV antigen and genome in mouse salivary glands. Evaluation of an autonomous HDV infection in an intact system will define the ability of HDV to initiate a SS-like phenotype. The third aim of this grant will deliver a test to detect low-level HDV infection specifically in salivary gland tissue and identify correlations between levels of HDV in salivary gland and those identified in serum or saliva. Identification of HDV sequence and antigen in the salivary glands of pSS patients is a significant discovery in the field of Sjgren's syndrome research and stands to greatly impact the current therapeutic approaches used to treat this autoimmune disease.